Grant funds new ALS treatment approach targeting TDP-43 pathway
Acurastem to study SYF2-based therapy in collaboration with academic labs
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- Acurastem received a grant to develop SYF2-targeting therapies for ALS.
- ALS involves toxic TDP-43 protein clumps, and SYF2 helps regulate TDP-43 function.
- The project will test antisense oligonucleotides designed to lower SYF2 levels in cells.
Acurastem has received a research grant from Target ALS to develop potential therapies for amyotrophic lateral sclerosis (ALS) that target SYF2, a protein involved in regulating TDP-43 function.
Abnormalities in the TDP-43 protein are a hallmark of ALS and are believed to play a central role in the disease’s underlying biology. Because TDP-43 dysfunction is seen in the vast majority of ALS cases, SYF2-targeting approaches could potentially benefit many people with the condition.
The two-year project, titled “Advancing SYF2 Antisense Oligonucleotides to Restore TDP-43 Function,” will be carried out in collaboration with researchers at Johns Hopkins University and Mayo Clinic in Jacksonville, Florida. Financial details of the grant were not included in the announcement.
“For most people living with ALS, the disease is driven by the dysfunction of TDP–43, but there are still no effective treatments that target this core [disease-driving mechanism],” Sam Alworth, co-founder and CEO of Acurastem, said in a company press release. “This project will accelerate our understanding of SYF2 biology and help lay the groundwork for future SYF2-targeted medicines.”
Understanding TDP-43 and its role in ALS
ALS is marked by the progressive loss of motor neurons, the nerve cells that control voluntary movement. In the vast majority of patients, these cells accumulate toxic clumps of the TDP-43 protein, a hallmark of the disease.
Under normal conditions, TDP-43 resides in the nucleus, where DNA is stored, and helps process messenger RNA (mRNA), which carries genetic instructions needed to produce proteins.
In ALS, however, TDP-43 becomes mislocalized and forms toxic aggregates in the cytoplasm, the fluid outside the nucleus. This disrupts normal RNA processing and is associated with motor neuron damage.
Recent research has identified SYF2, a protein also involved in RNA processing, as an important regulator of TDP-43 activity. Reducing SYF2 levels has been shown in lab models to help restore normal TDP-43 activity and reduce signs of neurodegeneration.
These findings suggest that therapies targeting SYF2 may represent a promising approach for addressing TDP-43-related disease mechanisms in ALS.
New project will test SYF2-targeted ALS therapies
The newly funded project will explore this approach using antisense oligonucleotides, short strands of genetic material designed to bind to a specific mRNA and block the production of the corresponding protein. In this case, the ASOs are designed to bind to SYF2 mRNA and reduce the amount of SYF2 protein produced.
The work will combine expertise from several groups. A team led by Philip Wong, PhD, at Johns Hopkins University, will study TDP-43-dependent RNA splicing (how genes are processed into proteins) and help identify potential fluid biomarkers. Meanwhile, Wilfried Rossoll, PhD, at Mayo Clinic Jacksonville, and his team will focus on proteomics and neuroproteostasis (how cells maintain healthy proteins) related to TDP-43 proteinopathy.
Acurastem will contribute its patient-derived motor neuron models and its SYF2-targeted antisense oligonucleotides. Using its iNeuroRx platform — a patient-based system built on cells derived from people with ALS — the company is able to reproduce key features of the disease in the lab, enabling researchers to test potential treatments.
The company is also developing other antisense therapies for ALS, including AS-241, a therapy designed to help restore normal function of UNC13A, a protein whose activity is disrupted when TDP-43 is not working properly.
